The tong-term goal of our research is to investigate how the intracellular signaling circuitry is wired in response to specific extracellular stimuli, thereby providing rationale and novel strategies for prevention and treatment of human diseases including cancer. JNK plays an central role in numerous diseases and cancer but the underlying molecular mechanisms are not completely understood. In this proposal, we will study the molecular mechanism by which the zinc finger protein Mizi, a novel timulus-specific modulators r regulators (SMOR) in the JNK signalsome, selectively regulates TNIF-induced JI'4K activation and apoptosis. Using multifaceted approaches, we have recently discovered that Mizi is a novel component of the JNK signalsorne and negatively regulates TNF-induced JNK activation and cell death through suppression of TRAF2 K63-linked polyubiquitination. Mizi -mediated inhibition is highly specific, as it inhibits activation of JNK but not other mitogen-activated protein kinases (MAPK5) or IkappaB kinase (lKK) by TNF and only inhibits JNK activation by TNF but not other known JNK inducers. We hypothesize that Mizi is a novel SMOR that selectively regulates TNFinduced JNK activation and apoptosis. This proposal is novel, as it will determine the molecular mechanism by which Mizi regulates TNF-induced JNK1 activation, to elucidate the molecular mechanism by which Mizi itself is inactivated by TNF. This study will put forward a novel paradigm regarding the molecular mechanism by which the TNF signaling circuitry is integrated and will also provide novel rationale in the developing strategies of prevention and treatment of apoptosis-related human diseases including cancer.